This application for small grant funding is a proposal to measure levels of the thyroid hormone transport peptide transthyretin (TTR) in the CSF of patients with refractory depression. Evidence has suggested for many years that at least a subgroup of depressed patients has subtle signs of decreased thyroid function, manifested mainly by exaggerated TSH response to TRH stimulation, elevated CSF TRH level, and elevated levels of antithyroid antibodies. Standard peripheral measures of thyroid hormone, however, are usually normal. We and others have speculated that some depressed patients may have a selective central hypothyroidism. It is now known that thyroid hormone is transported to the central nervous system by TTR. In a preliminary study involving eight hospitalized depressed patients who had failed to respond to conventional therapy we found significantly lower levels of TTR in CSF compared to a control group. this suggests that reduced transport of thyroid hormone to the central nervous system may occur in depression, leading to a state of central but not peripheral hypothyroidism. such an abnormality would theoretically lead to increased production of TRH. Methodological considerations limit the generalizability of our preliminary finding and we therefore wish to do a pilot study of TTR level in depression with the following goals: 1) to replicate our finding of reduced CSF TTR in refractory depression, 2) to determine if CSF TTR level is associated with any other abnormality in thyroid function, 3) to see if serum TTR level is correlated with CSF TTR level, and 4) to investigate the possibility that particular clinical features, such as motoric retardation, lethargy, and obesity, are characteristic of low CSF TTR in depressed patients. The proposed research should show whether CSF TTR is indeed low in at least a subgroup of depressed patients and will also introduce TTR measurement to psychiatric research. follow-up studies are suggested including expanding the patient group to include other forms of depression and treating depressed patients with low CSF TTR with thyroid hormone to see if this will correct the central deficit.